Average rates of protein catabolism in diabetes and starvation are increased by 50-150% in insulin-sensitive tissues. Our overall objectives are to study the characteristics and possible causes of this enhanced protein degradation. We have previously reported that several general characteristics of normal protein catabolism are strikingly altered in liver and muscle of diabetic or starved rats. In several normal tissues there are correlations between protein molecular weight and half-life, net charge and half-life, and carbohydrate content and half-life. Each of these relationships are absent during the enhanced protein breakdown caused by diabetes and starvation. We have recently found under a variety of conditions and using several different proteolytic enzymes that cellular proteins from normal and diabetic or starved animals are equally sensitive to proteolytic attack. It seems likely, therefore, that the enhanced degradation in diabetes and starvation results from some change in the cellular systems responsible for protein degradation rather than in the structure of the proteins per se. We are now developing a system of nonproliferating primary liver cell cultures to examine possible changes in the proteolytic systems within cells in response to nutrient or hormone deprivation. We also hope to define the exact hormonal and nutritional imbalances in diabetes that may contribute to the enhanced protein catabolism. Eventually we aim to define the biochemical reasons for the rapid degradation of proteins that occurs in diabetes and starvation.